Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion in Chimeric Antigen Receptor T-cell Immunotherapy (CAR-T): a Randomized Trial.

Official title

Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion in CAR-T Therapy: a Randomized Trial

Overview

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).

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).

Interventions

• 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)
• 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.

Primary outcome measures

• 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) [Time frame: 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 [Time frame: 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 [Time frame: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion]

Secondary outcome measures (3)

• Best lymphoma response at 3 months post-CAR-T infusion [Time frame: From the CAR-T infusion until week 15 (inclusive) post-CAR-T infusion]
• Progression-free survival (PFS) [Time frame: 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 frame: From CAR-T infusion to death, up to 3.25 years after CAR-T infusion of the first patient]

Eligibility criteria

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

Switzerland · 9 centers

• Kantonsspital Aarau — Aarau
• Universitätsspital Basel — Basel
• Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI) — Bellinzona
• Inselspital Bern - Universitätsklinik für Medizinische Onkologie — Bern
• Kantonsspital Graubünden — Chur
• Les hôpitaux universitaires de Genève — Geneva
• Luzerner Kantonsspital — Lucerne
• HOCH Health Ostschweiz - Kantonsspital St. Gallen — Sankt Gallen
• … and 1 more center

Identifiers

NCT: NCT07593482 · SCI-003_FC-BALANCE · 2026-525792-36-00 · U1111-1335-8513

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗