A phase II study of MT-3724, a novel CD20-targeting engineered toxin body, to evaluate safety, pharmacodynamics, and efficacy in subjects with relapsed or refractory diffuse large B-cell lymphoma.

Abstract

TPS8074 Background: Engineered toxin bodies (ETBs) are comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to antibody-like binding domains. ETBs work through novel mechanisms of action and are capable of forcing internalization, self-routing through intracellular compartments to the cytosol, and inducing potent cell-kill via the enzymatic and permanent inactivation of ribosomes. MT-3724 represents a novel ETB modality comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A. It is capable of efficient internalization once bound to CD20 and can induce potent direct cell-kill via enzymatic ribosome inactivation. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma (r/rDLBCL). Methods: The primary objective of this single-arm, Phase 2 study (NCT02361346) is to determine the efficacy of MT-3724 monotherapy in r/rDLBCL based on overall response rate (ORR), defined as the proportion of subjects with a complete/partial response according to the Lugano criteria, as assessed by independent, central review. Key secondary objectives include safety, progression-free survival, investigator‐assessed ORR, duration of response, overall survival, and pharmacodynamics. Adverse events will be assessed and documented according to Common Terminology Criteria for Adverse Events version 5.0. Key eligibility criteria include adult subjects with histologically confirmed, r/rDLBCL, with ≥2 prior standard of care systemic NHL treatment regimens, and ≥1 measurable lesion. As rituximab and other CD20-targeting antibodies compete with MT-3724 for the same CD20 domain, minimum washout periods from these agents must be observed. Subjects remain eligible post stem cell transplant or chimeric antigen receptor T-cell therapy. Subjects will receive 50 µg/kg MT-3724 IV over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. The anticipated sample size is N = 100. Interim analyses will be performed to confirm minimum efficacy thresholds based on the encouraging data observed in the completed phase 1 portion of the study [Hamlin et al. Blood 2019;134(Suppl 1):4098]. Multiple global sites are enrolling subjects. Clinical trial information: NCT02361346 .

Shiga Toxins as Antitumor Tools

“…These ETBs consist of a modified Stx1 catalytic subunit A genetically fused to a specific single-chain variable fragment (scFv). The first ETB produced, MT-3724, recognizes CD20-expressing cells and is currently in phase II trials for the treatment of DLBCL (diffuse large cell B lymphoma) as a single agent [88] or in combination with lenalidomide (NCT03645395) or gemcitabine/oxaliplatin (NCT03488251). According to the preliminary results, when used in combination with lenalidomide, it yielded complete responses in two of the seven patients tested, partial responses in three patients, stable disease in one patient and progressive disease observed in the final patient [89].…”

Novel Therapies for Relapsed or Refractory Diffuse Large B-Cell Lymphoma

“…MT-3724 is a novel Engineered Toxic Body (ETB) comprised of a proprietarily engineered form of Shiga-like Toxin A subunit (SLT-A) genetically fused to an antibody-like binding domain that binds CD20. ETBs work though a novel mechanism of action whereby the internalization of the fragment when bound to CD20 delivers the toxin intracellularly where ribosomal inactivation leads to targeted cell death [50,51]. MT-3724 is currently being studied in three ongoing Phase 2 studies for relapsed and refractory DLBCL.…”