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

Bendamustine and the combination of fludarabine/cyclophosphamide are fully authorized chemotherapy agents in Switzerland for lymphoma treatment and currently used in routine clinical practice as lymphodepletion strategy before CAR-T immunotherapy, as supported by retrospective studies and clinical experience across multiple centers. None of the drugs described in this protocol are being used at unapproved doses, or in an investigational formulation. Both lymphodepletion regimens have a known safety profile and the risks and burdens imposed on participants do not exceed those encountered in routine CAR-T therapy management, as all procedures (including monitoring, supportive care, and follow-up assessments) align with standard clinical practice. Based on these assumptions, this protocol is designed to investigate the use of bendamustine as an alternative lymphodepletion therapy (which is a part of CAR-T immunotherapy protocol).

Study Overview

• Status: Not yet recruiting
• Conditions: B-cell Lymphoma
• Intervention / Treatment: Drug: bendamustine hydrochloride; Drug: Cyclophosphamide; Drug: Fludarabine

Detailed Description

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).

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Ana Bello Gamboa; Phone Number: +41 31 389 91 91; Email: trials@swisscancerinstitute.ch

Study Locations

• Switzerland
  • Aarau, Switzerland, 5001
    • Kantonsspital Aarau
    • Contact: Martina Dickenmann, MD; Phone Number: +41 79 391 22 75; Email: martina.dickenmann@ksa.ch
    • Principal Investigator: Martina Dickenmann, MD
  • Basel, Switzerland, 4056
    • Universitätsspital Basel
    • Contact: Andreas Holbro, MD; Phone Number: +41 61 265 25 25; Email: Andreas.Holbro@usb.ch
    • Principal Investigator: Andreas Holbro, MD
  • Bellinzona, Switzerland, 6500
    • Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
    • Contact: Georg Stüssi, Prof; Phone Number: +41 91 811 87 78; Email: Georg.Stuessi@eoc.ch
    • Principal Investigator: Georg Stüssi, Prof
  • Bern, Switzerland, 3010
    • Inselspital Bern - Universitätsklinik für Medizinische Onkologie
    • Contact: Marc Wehrli, MD; Phone Number: +41 31 632 41 11; Email: marc.wehrli@insel.ch
    • Principal Investigator: Marc Wehrli, MD
  • Chur, Switzerland, 7000
    • Kantonsspital Graubünden
    • Contact: Ulrich Mey, PD; Phone Number: +41 81 256 71 70; Email: ulrich.mey@ksgr.ch
    • Principal Investigator: Ulrich Mey, MD
  • Geneva, Switzerland, 1211
    • Les hôpitaux universitaires de Genève
    • Contact: Federico Simonetta, MD; Phone Number: +41 22 372 38 38; Email: federico.simonetta@unige.ch
    • Principal Investigator: Federico Simonetta, MD
  • Lucerne, Switzerland, 6004
    • Luzerner Kantonsspital
    • Contact: Ramona Merki, MD; Phone Number: +41 41 205 51 47; Email: ramona.merki@luks.ch
    • Principal Investigator: Ramona Merki, MD
  • Sankt Gallen, Switzerland, 9007
    • HOCH Health Ostschweiz - Kantonsspital St. Gallen
    • Contact: Martin Fehr, MD; Phone Number: +41 71 494 62 69; Email: martin.fehr@h-och.ch
    • Principal Investigator: Martin Fehr, MD
  • Zurich, Switzerland, 8032
    • Klinik für Hämatologie und Onkologie Hirslanden Zürich
    • Contact: Christoph Renner, Prof; Phone Number: +41 43 387 37 80; Email: christoph.renner@kho.ch
    • Principal Investigator: Christoph Renner, Prof

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: Experimental Arm; Bendamustine	Drug: bendamustine hydrochloride; Dose: 90 mg/m² body surface area; Route: Intravenous infusion; Administration: Infused over 30-60 minutes in 500 mL normal saline or 5% dextrose; Pre-medication: Standard institutional protocols for bendamustine administration (typically antiemetics)
Active Comparator: Arm B: Control Arm; Fludarabine/Cyclophosphamide	Drug: Cyclophosphamide; Administration: Intravenous infusion per institutional protocols and product guidelines.; Dose: according to the specification described in the prescription information sheet of the CAR-T product used.; Drug: Fludarabine; Administration: Intravenous infusion per institutional protocols and product guidelines.; Dose: according to the specification described in the prescription information sheet of the CAR-T product used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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)	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: Febrile neutropenia	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	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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best lymphoma response at 3 months post-CAR-T infusion	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.	From the CAR-T infusion until week 15 (inclusive) post-CAR-T infusion
Progression-free survival (PFS)	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]
Overall survival (OS)	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.	From CAR-T infusion to death, up to 3.25 years after CAR-T infusion of the first patient

Collaborators and Investigators

• Sponsor: Swiss Cancer Institute
• Investigators: Study Chair: Benjamin Kasenda, PD Dr. med. Dr. phil., University Hospital Basel (USB); Study Director: Guido Ghilardi, Ente Ospedaliero Cantonale (EOC)

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): March 1, 2029
• Study Completion (Estimated): March 1, 2030

Study Registration Dates

• First Submitted: May 4, 2026
• First Submitted That Met QC Criteria: May 13, 2026
• First Posted (Actual): May 18, 2026

Study Record Updates

• Last Update Posted (Actual): May 18, 2026
• Last Update Submitted That Met QC Criteria: May 13, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Bendamustine; LBCL; B-cell malignancy; Large B-cell lymphoma; Chimeric antigen receptor (CAR) T-cell therapy; Fludarabine/Cyclophosphamide; lymphodepletion in CAR-T therapy
• Additional Relevant MeSH Terms: Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Hemic and Lymphatic Diseases; Lymphoma, B-Cell; Organic Chemicals; Heterocyclic Compounds; Benzimidazoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Hydrocarbons; Acids, Acyclic; Carboxylic Acids; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds; Butyrates; Bendamustine Hydrochloride; Cyclophosphamide; fludarabine
• Other Study ID Numbers: SCI-003_FC-BALANCE; 2026-525792-36-00 (Ctis); U1111-1335-8513 (Other Identifier: ICTRP)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No