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
調査の概要
詳細な説明
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).
研究の種類
入学 (推定)
段階
- フェーズ2
連絡先と場所
研究連絡先
- 名前：Ana Bello Gamboa
- 電話番号：+41 31 389 91 91
- メール：trials@swisscancerinstitute.ch
研究場所
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Aarau、スイス、5001
- Kantonsspital Aarau
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コンタクト：
- Martina Dickenmann, MD
- 電話番号：+41 79 391 22 75
- メール：martina.dickenmann@ksa.ch
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主任研究者：
- Martina Dickenmann, MD
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Basel、スイス、4056
- Universitätsspital Basel
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コンタクト：
- Andreas Holbro, MD
- 電話番号：+41 61 265 25 25
- メール：Andreas.Holbro@usb.ch
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主任研究者：
- Andreas Holbro, MD
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Bellinzona、スイス、6500
- Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
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コンタクト：
- Georg Stüssi, Prof
- 電話番号：+41 91 811 87 78
- メール：Georg.Stuessi@eoc.ch
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主任研究者：
- Georg Stüssi, Prof
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Bern、スイス、3010
- Inselspital Bern - Universitätsklinik für Medizinische Onkologie
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コンタクト：
- Marc Wehrli, MD
- 電話番号：+41 31 632 41 11
- メール：marc.wehrli@insel.ch
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主任研究者：
- Marc Wehrli, MD
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Chur、スイス、7000
- Kantonsspital Graubunden
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コンタクト：
- Ulrich Mey, PD
- 電話番号：+41 81 256 71 70
- メール：ulrich.mey@ksgr.ch
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主任研究者：
- Ulrich Mey, MD
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Geneva、スイス、1211
- Les hôpitaux universitaires de Genève
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コンタクト：
- Federico Simonetta, MD
- 電話番号：+41 22 372 38 38
- メール：federico.simonetta@unige.ch
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主任研究者：
- Federico Simonetta, MD
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Lucerne、スイス、6004
- Luzerner Kantonsspital
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コンタクト：
- Ramona Merki, MD
- 電話番号：+41 41 205 51 47
- メール：ramona.merki@luks.ch
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主任研究者：
- Ramona Merki, MD
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Sankt Gallen、スイス、9007
- HOCH Health Ostschweiz - Kantonsspital St. Gallen
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コンタクト：
- Martin Fehr, MD
- 電話番号：+41 71 494 62 69
- メール：martin.fehr@h-och.ch
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主任研究者：
- Martin Fehr, MD
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Zurich、スイス、8032
- Klinik für Hämatologie und Onkologie Hirslanden Zürich
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コンタクト：
- Christoph Renner, Prof
- 電話番号：+41 43 387 37 80
- メール：christoph.renner@kho.ch
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主任研究者：
- Christoph Renner, Prof
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参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Arm A: Experimental Arm
Bendamustine
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アクティブコンパレータ：Arm B: Control Arm
Fludarabine/Cyclophosphamide
|
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
|
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)
時間枠：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
時間枠：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
時間枠：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
|
二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Best lymphoma response at 3 months post-CAR-T infusion
時間枠：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)
時間枠：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)
時間枠：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
|
協力者と研究者
スポンサー
捜査官
- スタディチェア：Benjamin Kasenda, PD Dr. med. Dr. phil.、University Hospital Basel (USB)
- スタディディレクター：Guido Ghilardi、Ente Ospedaliero cantonale (EOC)
研究記録日
主要日程の研究
研究開始 (推定)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- SCI-003_FC-BALANCE
- 2026-525792-36-00 (Ctis)
- U1111-1335-8513 (その他の識別子：ICTRP)
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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