Background: Engineered toxin bodies (ETBs) are a distinct class of targeted immunotoxins in development by Molecular Templates as anticancer therapeutics. ETBs have a novel mechanism of action that drives a potent and targeted response mediated by antibody-like binding, cellular internalization, and enzymatic ribosomal inhibition via the delivery of a Shiga-like toxin subunit A (SLTA). MT-3724 comprises an anti-CD20 single chain variable fragment genetically fused to SLTA with an approximate molecular weight of 55 kDa and is being developed for the treatment of relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). MT-3724 is currently being studied in three ongoing phase 1/2 studies for r/rDLBCL.

Methods: MT-3724 is being evaluated in this phase 2a study (NCT03645395) in combination with LEN in adult patients with histologically confirmed, relapsed, or refractory CD20+ B-cell NHL. The primary objectives of this study are to determine the safety and tolerability, including the maximum tolerated dose (MTD), of MT-3724+LEN. Secondary objectives include pharmacokinetics, pharmacodynamics, immunogenicity, and tumor response. The study is being conducted in two parts. Part 1 includes MT-3724 dose escalation over 5 dose cohorts according to the modified 3+3 design and will include up to 24 subjects with CD20+ NHL. Part 2 is designed to assess the safety and tolerability of MT-3724+LEN in the MTD Expansion Cohort, where the dose declared as MTD of MT-3724 in Part 1 will be given in combination with LEN in up to 40 subjects with CD20+ r/rDLBCL. Eligible subjects must have received at least one approved therapy for NHL and must have measurable disease by Lugano criteria. Subjects who have progressed following CAR T-cell therapy, autologous or allogeneic stem cell transplant are also eligible. Serum rituximab level must be negative (<500 ng/mL) at screening because it competes with MT-3724 for binding to CD20. In the first 2 dose cohorts (10 and 25 ug/kg/dose) of Part 1, subjects received MT-3724 IV infusions over 1 hour three times weekly for 2 weeks and LEN (20 mg daily) on Days 1-21 of each 28-day treatment cycle for Cycles 1 and 2. In subsequent cycles, MT-3724 was administered once weekly with continued LEN dosing on Days 1-21. Because of 2 dose-limiting toxicities (grade 2 capillary leak syndrome) in Cohort 2, the dose in Cohort 3 was reduced to 20 ug/kg/dose. The protocol was amended so that in future Cohorts 4 and 5 (25 and 50 ug/kg/dose), MT-3724 will be dosed biweekly for 2 weeks for Cycles 1 and 2 and then once weekly for subsequent cycles. The study is recruiting subjects at multiple study centers.

Citation Format: Jason Tache, Deborah A. Katz, Amitabha Mazumder, David Peace, Christine Burnett, Thomas Strack, Elizabeth Bay, Roger Waltzman, Seung Lee. A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-63.