Trials in Progress: Carman - an International, Randomized Phase II Study 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 (Arm A) As Compared to Standard of Care Induction and Maintenance (Arm B)

Mantle cell lymphoma (MCL) is a rare lymphoma subtype that accounts for 8% of Non-Hodgkin lymphomas and is still considered incurable. Prognostic parameters such as TP53 alterations, high Ki-67 proliferation index, blastoid or pleomorphic morphologic characteristics and/or high-risk combined MCL International Prognostic Index (MIPI-c) are associated with poor outcome. Chemoimmunotherapy and targeted therapies such as Bruton's tyrosine kinase inhibitors (BTKi) may induce remission in such high-risk patients, but early relapses frequently occur and actually there is a unmet need for improved treatment. The anti-CD19 chimeric antigen receptor T-cell (CAR-T) product brexucabtagene autoleucel has demonstrated encouraging efficacy in relapsed or refractory aggressive MCL, failing to previous BTKi therapy after up to 5 prior regimens. However, restricting CAR-T cell therapy to subsequent treatment lines increases the risk of disease evolution causing potentially limited treatment efficacy. Thus, applying CAR T cells in first line, targeting more susceptible malignant cells, seems reasonable. The combination with Ibrutinib is likely to induce synergistic effects with CAR-T-cells by increasing the viability and expansion of T-cells while inhibiting T-cell exhaustion.

The European Mantle Cell Lymphoma (EMCL) Network has developed a phase II study concept exploring early treatment intensification through the integration of brexucabategene autoleucel into the first line treatment of high-risk MCL patients. In the control arm, patients are treated analogous to the TRIANGLE study (EudraCT#: 2014-001363-12), which recently has established the use of Ibrutinib in combination with intensive induction and maintenance in younger patients with MCL.

CARMAN is a randomized controlled, international, multicenter, open-label phase II trial (clinicaltrials.gov: NCT06482684) evaluating the efficacy and safety of brexucabtagene autoleucel following an abbreviated induction (3 cycles of Ibrutinib + Rituximab (IR) and 2 cycles of Ibrutinib + R-CHOP in patients not achieving at least a PR to IR), and 6 months Ibrutinib maintenance starting 3 months post CAR-T-treatment (Arm A) as compared to standard of care chemoimmunotherapy combined with Ibrutinib induction (patients ≤ 65 years will receive 3 cycles R-CHOP+Ibrutinib/ 3 cycles R-DHAP alternating, followed by ASCT if appropriate and Ibrutinib/Rituximab maintenance. Patients ≥65 years will receive 6 cycles of Bendamustine and Rituximab + Ibrutinib or R-CHOP + Ibrutinib without ASCT) and 2 years maintenance with Ibrutinib with or without Rituximab maintenance, according to national guidelines (Arm B). The maximum duration of the study will be 7 years, with up to 2 years recruitment, 2.5 years of treatment (Arm B) and up to 2.5 years additional follow-up. The primary endpoint is the failure-free survival from randomization to stable disease or progressive disease after end of induction, or death from any cause. A total number of 150 patients (18-75 years, ECOG ≤2) with previously untreated stage II-IV MCL, at least one high-risk feature (MIPI-c high intermediate or high risk and/or TP53-mutation and/or p53-overexpression by immunohistochemistry) and at least 1 measurable lesion according to the Lugano Response Criteria will be enrolled (approx. 75 in each arm) in about 40 sites in 5 countries: Germany, France, Spain, Czech Republic and The Netherlands. The primary statistical evaluation aims to reject the null hypothesis of equal FFS-probabilities in the two trial arms on a two-sided significance level of 10% and is planned to have 90% power to reject the null hypothesis if the true FFS-hazard ratio is 0.558 for A vs. B. One efficacy interim analysis is planned after the observation of half of the projected events.

The scientific program includes analysis for MRD, molecular risk profiling, immune reconstitution and quality of life.

As of July 31st, the first patients have been recruited in Germany and activation of all sites is planned until end of 2024.