A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies

Introduction: IGM-2323 is the first engineered high-affinity, high-avidity bispecific IgM monoclonal antibody TCE to be tested in the clinic. It has 10 binding domains for CD20 and a single binding domain for CD3 and is designed to bind irreversibly to CD20-high and low-expressing cells with more physiologic stimulation to T cells, which may mitigate cytokine release syndrome (CRS)-related toxicity and broaden the therapeutic window. IGM-2323 may act by multiple mechanisms: T-cell dependent cytotoxicity, complement dependent cytotoxicity, and enhanced immune modulation via IFNγ-dominant cytokine stimulation. This phase 1 study is exploring the safety and activity of IGM-2323 using a dose titration schedule intended to optimize repeatable immune stimulation while minimizing toxicity. Methods: This first-in-human Phase 1 study is a global, multicenter, open-label, dose escalation evaluating safety, tolerability, PK, and preliminary efficacy (NCT04082936). Adults with relapsed or refractory CD20 + B-cell NHL with ≥ 2 prior systemic therapies, adequate organ function, and ECOG 0-1 are eligible. IGM-2323 is given IV on Days 1, 8, and 15 of 21-day cycles until disease progression or unacceptable toxicity. Treatment can continue beyond progression if the patient (pt) has benefitted from treatment and intra-patient dose escalation is allowed. This study also utilizes a dose titration scheme where a starting dose is given on Day 1, then higher subsequent doses are given up to a plateau dose. If a pt has symptoms of CRS, the same dose may be repeated, and a higher dose is not given until the dose is well tolerated. Results: As of April 30, 2021, 29 pts have been enrolled: 12 at 5 fixed dose levels (0.5, 2.5, 10, 30, 100 mg) and 17 at 5 dose titration levels (50/100, 50/200, 50/300, 50/600, 50/1000 mg)*. NHL subtypes include: 13 follicular (FL), 11 diffuse large B-cell (DLBCL), 3 mantle cell (MCL), and 2 marginal zone (MZL). Median age is 66 (range, 36-84) and median prior therapies is 3 (range, 2-7). 2 pts had prior autologous transplant and 7 had prior CAR-T. All 29 pts received at least one dose and are safety evaluable. There were no DLTs and no neurotoxicity AEs. No pts discontinued due to AE. There were 3 drug-related SAEs (1 each Gr1/2/3 CRS by ASTCT). 16 pts discontinued treatment: 2 pt/investigator decision and 14 PD. The 13 pts still on treatment have received a median of 9 doses (range, 1-42). At fixed dose levels, 5 of 12 pts had a CRS event, primarily gr