MB-105 Receives Orphan Drug Designation in Relapsed/Refractory CD5+ T-Cell Lymphoma

The first-in-class CD5-targeted CAR-T cell therapy MB-105 has received orphan drug designation from the FDA for the treatment of patients with relapsed/refractory CD5-positive T-cell lymphoma.1

The agent is being examined in patients with relapsed/refractory mature T-cell malignancies in the phase 1 MAGENTA trial (NCT03081910).2,3 Findings from the study showed that patients with T-cell lymphoma who received MB-105 (n = 9) achieved an overall response rate (ORR) of 44%, including 2 patients who experienced complete responses.2

In terms of safety, the most common grade 3 or higher adverse effects that occurred were cytopenias. There were no instances of grade 3 or greater cytokine release syndrome (CRS) or neurologic events. Rapidly progressive disease caused the deaths of 2 patients during the immediate toxicity evaluation.

“Beyond an important regulatory milestone, securing orphan drug designation for MB-105 from the FDA underscores the critical need for new therapeutic options for patients with T-cell lymphoma,” Sarah Hein, cofounder and chief executive officer of March Biosciences, stated in a news release.1 “Currently, patients with treatment-resistant or recurrent T-cell cancers face an extremely poor prognosis. The MB-105 phase 1 trial has shown promising safety and efficacy signals in [patients with] relapsed/refractory T-cell lymphoma. This designation further validates our development strategy as we prepare to initiate our phase 2 clinical trial in early 2025.”

MB-105 employs a novel CAR design that allows for the selective targeting of malignant cells and the preservation of some normal T-cell function. The agent is being developed for the treatment of patients with CD5-positive hematologic malignancies, including T-cell lymphoma, T-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma.

MAGENTA was the first-in-human study of MB-105 in patients up to 75 years of age with CD5-expressing T-cell malignancies.3 In order to be eligible for the study, patients must have a life expectancy of over 12 weeks, an available human leukocyte antigen-matched allogeneic T-cell line Epstein-Barr virus-specific T-cell line, and hemoglobin levels of at least 7.0 g/dL. Patients in group A needed to be transplant naive or have experienced disease relapse post-allogeneic hematopoietic stem cell transplantation (HSCT) and those in group B needed to have experienced disease relapse post-allogeneic HSCT with a previous HSCT donor from whom allogeneic CAR T cells can be manufactured.

In both groups, MB-105 was evaluated at 3 dose levels: 1 × 107 cells/m2, 5 × 107 cells/m2, or 1 × 108 cells/m2. The primary end point was the rate of dose-limiting toxicities, and the secondary end point was ORR.

The confirmatory phase 2 MB-105-201 study (NCT06534060) will enroll adult patients with relapsed/refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma who have failed at least 1 prior systemic line of therapy for peripheral T-cell lymphoma or at least 2 prior lines for high-volume cutaneous T-cell lymphoma.4 Eligible patients also need to have adequate organ function and a Karnofsky performance status of at least 70%. Previous cell therapy or HSCT must be given at least 60 days prior to leukapheresis.

Eligible patients will enter screening 1 to 2 months prior to initiating treatment and will undergo leukapheresis approximately 1 month before treatment. Bridging therapy is permitted over the 3 weeks MB-105 is being manufactured. Once the CAR T agent arrives on site, patients will receive standard fludarabine/cyclophosphamide conditioning therapy, followed by 2 days of rest, rituximab (Rituxan) prophylaxis based on Epstein-Barr virus serostatus, and CAR-T infusion on day 0 as an outpatient treatment with standard supportive measures.

The trial will consist of 3 stages:a safety run-in to confirm tolerability of the phase 1 recommended dose of 5.0 x 107 cells in 6 patients, a Simon stage 1 portion which will require responses in at least 6 of 15 patients, and a Simon stage 2 portion that will enroll an additional 31 patients.

Patients will complete safety visits to monitor for CRS and immune effector cell-associated neurotoxicity syndrome for a week, twice weekly for the first month, then monthly until 6 months after treatment. Additional safety visits will take place at 9, 12, and 18 months, followed by an end of study visit at 2 years. Long term safety and efficacy follow-up will be conducted under a separate protocol.

The primary objectives of the study are to confirm the safety of the recommended dose of MB-105 in the safety run-in and to examine the efficacy of the agent in Simon stages 1 and 2 via independent central review using Lugano 2014 and global criteria. Secondary objectives include duration of response, overall survival, and the demonstration of manufacturing success.

References

1. March Biosciences receives FDA orphan drug designation for MB-105, a first-in-class CD5 CAR-T cell therapy, for T-cell lymphoma. News release. March Biosciences. January 28, 2025. Accessed January 29, 2025. https://www.globenewswire.com/news-release/2025/01/28/3016342/0/en/March-Biosciences-Receives-FDA-Orphan-Drug-Designation-for-MB-105-a-First-in-Class-CD5-CAR-T-Cell-Therapy-for-T-Cell-Lymphoma.html
2. Hill LC, Rouce RH, Wu MJ, et al. Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas. Blood. 2024;143(13):1231-1241. doi:10.1182/blood.2023022204
3. Autologous T-cells expressing a second generation CAR for treatment of T-cell malignancies expressing CD5 antigen (MAGENTA). ClinicalTrials.gov. Updated September 27, 2024. Accessed January 29, 2025. https://clinicaltrials.gov/study/NCT03081910
4. Iyer SP, Hill L, Horwitz S, et al. Confirmatory efficacy and safety evaluation of MB-105, a CD5.CAR T therapy: multicenter phase 2 study in patients with relapsed/refractory T cell lymphoma (R/R TCL). Blood. 2024;144(suppl 1):7223. doi:10.1182/blood-2024-201523