Trial in Progress: Odronextamab for the Treatment of Patients with Relapsed/Refractory Mantle Cell Lymphoma Following Prior BTK Inhibitor Therapy - a Cohort of the ELM-2 Study
Authors: Cho Seok-Goo , Kim Tae Min , Taszner Michal , Chen Tsai-Yun , Choudhry Aafia , Ufkin Melanie , Uppala Amulya , Sabir Ayesha , Mohamed Hesham , Ambati Srikanth , Bachy Emmanuel 
Published: December 2024

Background and Significance
Mantle cell lymphoma (MCL) is a heterogenous, incurable disease that encompasses approximately 3% of all non-Hodgkin lymphoma (NHL) cases (Teras LR et al. CA Cancer J Clin 2016). Treatment of patients with MCL can be challenging due to its high-risk molecular features, circulating tumor burden, and bone marrow involvement, and most patients relapse after receiving frontline chemoimmunotherapy (Kumar A et al. Blood Cancer J 2019). Treatment options for patients with relapsed/refractory (R/R) MCL after initial therapy include chimeric antigen receptor T-cell (CAR T) therapy and Bruton's tyrosine kinase inhibitors (BTKis); however, prognosis after BTKi discontinuation is poor, with a median overall survival (OS) of ~4 months (Hess G et al. Br J Haem 2022), representing an important unmet clinical need.
Odronextamab is an investigational off-the-shelf CD20×CD3 bispecific antibody that demonstrated encouraging clinical activity (objective response rate [ORR] 52%, complete response [CR] rate 31%) in patients with heavily pretreated R/R diffuse large B-cell lymphoma (DLBCL) in the Phase 2, open-label, multicenter ELM-2 study (NCT03888105; Ayyappan S et al. ASH 2023). Grade ≥3 treatment-emergent adverse events (TEAEs) were reported in 84% of patients, and 13% of patients had TEAEs (any grade) that led to treatment discontinuation. Odronextamab also demonstrated encouraging clinical activity (ORR 50%) in a cohort of 12 patients with MCL in the Phase 1 ELM-1 study (NCT02290951, Bannerji R et al. Lancet Haematol 2022). Patients with MCL have a high risk of cytokine release syndrome (CRS) when receiving T-cell engagers due to their circulating tumor burden and other high-risk features; this is reflected by the fact that in 12 patients receiving the initial 1/20 mg step-up regimen in ELM-1, 1 patient (1%) had a Grade 4 CRS event in the context of Grade 5 tumor lysis syndrome. Here, we report the study design used in the R/R MCL cohort of ELM-2.
Study Design and Methods
ELM-2 (NCT03888105) is an ongoing study of odronextamab in patients with R/R B-cell NHL (B-NHL) that comprises 5 disease-specific cohorts, each with independent parallel enrollment: DLBCL, follicular lymphoma, MCL after BTKi therapy, marginal zone lymphoma, and other B-NHL. Patients are being recruited at sites across North America, Europe, and Asia-Pacific regions. Eligibility criteria for the MCL cohort include: age ≥18 years; R/R to ≥1 prior line of systemic therapy, including a BTKi; Eastern Cooperative Oncology Group performance status ≤1; and adequate bone marrow and hepatic function. Patients who have received prior allogeneic stem cell transplant, or any systemic anti-lymphoma therapy within 28 days of initiation of study treatment, are excluded.
The MCL cohort will include 78 patients who will receive intravenous odronextamab monotherapy until disease progression, unacceptable toxicity, or another protocol-defined reason for treatment discontinuation. Following the high rates of observed Grade ≥3 CRS in patients with MCL, including a fatal event in a patient receiving the initial 1/20 mg step-up regimen, enrollment was paused, and the step-up regimen was revised to 0.7/4/20 mg to help further mitigate the risk of CRS.
Patients will receive odronextamab in 21-day cycles, with 0.7/4/20 mg step-up dosing in Cycle 1, then 160 mg on Day 1, 8, and 15 of Cycles 2-4. Post-Cycle 4, maintenance dosing of 320 mg once every 2 weeks (Q2W) will be administered. Patients with a durable CR for ≥9 months will switch to Q4W dosing.
The primary endpoint is ORR according to Lugano classification, assessed by independent central review. Key secondary endpoints include ORR by investigator evaluation; CR rate; progression-free survival; OS; duration of response; disease control rate; safety; pharmacokinetics; and patient-reported quality of life outcomes.
As of July 2024, 14 patients with MCL have been enrolled.