Trials in progress: CARMAN – study protocol of a randomized controlled, international, multicenter, open-label phase II trial evaluating early treatment intensification in patients with high-risk mantle cell lymphoma using CAR-T-cell treatment after an abbreviated induction therapy with rituximab and ibrutinib and 6 months ibrutinib maintenance as compared to standard of care induction and maintenance

Background Brexucabtagene-autoleucel (brexu-cel) is an anti-CD19 chimeric antigen receptor T-cell (CAR-T) product approved for relapsed/refractory Mantle Cell Lymphoma (MCL) after two prior treatment lines, including Bruton tyrosine kinase inhibitors (BTKi). Patients with high-risk (hr) disease—defined by high-intermediate or high-risk MIPI-c, p53 overexpression, or TP53 alterations—have a poor prognosis, underscoring the need for improved first-line strategies. The European Mantle Cell Lymphoma Network therefore designed a phase II trial to investigate the incorporation of brexu-cel into first-line therapy for hr MCL. Methods CARMAN is a randomized controlled, international, multicenter, open-label phase II trial evaluating efficacy, safety, and tolerability of an abbreviated induction followed by first-line brexu-cel and 6 months Ibrutinib maintenance (Arm A) as compared to standard of care induction and maintenance (Arm B). In Arm A, induction consists of two cycles of ibrutinib plus rituximab (I + R) followed by two cycles of R-CHOP plus ibrutinib (I). R-CHOP + I may be omitted in patients achieving complete or partial remission after two cycles of I + R, who then receive one additional I + R cycle before brexu-cel infusion and I maintenance. Arm B comprises a TRIANGLE-like regimen based on age, fitness, and investigator choice (alternating R-CHOP plus ibrutinib/R-DHAP or IR-bendamustine), followed by IR maintenance. Overall, 150 patients from five European countries are randomized 1:1. The primary endpoint is failure-free survival from randomization, with failure event defined as the earliest of stable disease at the end of induction (Arm B, or Arm A if brexu-cel is not infused) or within 12 weeks from CAR-T-cell infusion (Arm A), disease progression after induction, or death from any cause. Secondary endpoints include efficacy (overall and complete response rates and PET-negative CR rate 6 months from randomization as assessed according to Lugano criteria, molecular remission rate as measured by MRD), safety and tolerability (adverse events graded according to CTCAE), and patient-reported quality of life as measured by the EORTC-QLQ-C30 and EORTC-QLQ-NHL-HG29 questionnaires. Discussion When complete, CARMAN will provide important information on efficacy and safety in first-line CAR-T cell therapy in hr MCL and has the potential to prepare a practice changing confirmatory trial for these difficult-to-treat patients. Recruitment is ongoing. Trial registration EU clinical trial number: 2022-502405-15-00.