A Phase 2a Open-Label Study to Investigate Safety and Tolerability (including the MTD), Efficacy, Pharmacokinetics, Pharmacodynamics and Immunogenicity of MT-3724 in Combination with Gemcitabine and Oxaliplatin in Subjects with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma (2019)

Introduction: Approximately 40% of all newly diagnosed Diffuse large B-cell lymphoma (DLBCL) patients are either refractory or relapsed following initial therapy, and represent a population with high unmet need for new therapeutic strategies to achieve or regain disease remission. Because of the near ubiquity and persistence of CD20 expression in B-cell malignancies, there is strong rationale to develop compounds with novel mechanisms of action (MOA) targeting CD20. However, CD20's non-internalizing nature has, to date, leveraged only cytotoxic mechanisms such as antibody-dependent cellular cytotoxicity to which resistance can arise. MT-3724 is a novel engineered toxin body designed to overcome this limitation by combining the specific target selectivity of a single chain variable fragment with the lethality of a genetically fused Shiga-like toxin A subunit that facilitates both internalization and cell killing by inactivating ribosomal protein synthesis. MT-3724 has been shown to specifically bind and kill CD20+ malignant human B-cells in vitro (IC50 &lt;1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018). MT-3724 has been studied in a dose-escalation monotherapy trial (NCT02361346) and has achieved clinical response as monotherapy in subjects with relapsed NHL regardless of acquired resistance to other treatments. Given MT-3724's unique ability to kill CD20+ cells by ribosomal inhibition, combining MT-3724 with standard cytotoxic chemotherapy may provide enhanced benefit in NHL treatment. To evaluate this possibility, MT-3724 was tested in combination with selected cytotoxic compounds including gemcitabine and cisplatin in various CD20+ cell lines (Raji, SU-DHL-4, Daudi, HBL-1). MT-3724 showed synergistic cytotoxic effects with gemcitabine and mixed additive/synergistic or synergistic effects with cisplatin in all 4 cell lines. Based on these results and the known safety profile of MT-3724, gemcitabine and oxaliplatin (GEMOX) were chosen as combination agents to maximize anti-tumor effects in patients with CD20+ B-cell NHL while minimizing overlapping toxicity risks. Study Design and Methods: MT-3724 is being evaluated in this Phase 2a study (NCT03488251) in combination with GEMOX, in adult subjects with histologically confirmed, relapsed or refractory CD20+ B-cell NHL. The primary objective of this study is to determine the safety and tolerability including the maximum tolerated dose (MTD) of MT-3724+GEMOX. Secondary objectives include the assessment of pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and tumor response. The study will be conducted in two parts. Part 1 will include MT-3724 dose escalation according to a modified 3+3 design to identify the MTD of MT-3724 in combination with GEMOX and will include up to 24 subjects with histologically confirmed NHL. All subtypes of B-cell NHL are eligible for Part 1. Part 2 is designed to confirm the safety and tolerability of MT-3724 in the MTD Expansion Cohort, MT-3724 would be given in combination with GEMOX in up to 40 subjects with CD20+ DLBCL. In addition, the PK, PD, immunogenicity and tumor response of MT-3724 in combination with GEMOX. Eligible subjects will have histologically confirmed, relapsed or refractory CD20+ B-cell NHL that could benefit from MT-3724+GEMOX therapy. Subjects must have received all approved therapies for NHL that are applicable for the subject in the opinion of the treating physician and must have measurable disease by Lugano criteria. Subjects that are refractory to treatment are eligible, as well as patients who have progressed following CAR T-cell therapy, autologous- or allogeneic stem cell transplant. Residual rituximab causes MT-3724 to be ineffective as per the previous study experience therefore serum rituximab level must be &lt;500 ng/mL at screening so that the MOA of MT-3724 is not inhibited. Subjects will receive MT-3724 IV infusions over 1 hour in 3 successive dose cohorts (at 10, 20, and 50-µg/kg/dose) on Days 1, 3, 5, 8, 10 and 12 and will receive GEMOX (GEM 1000 mg/m2, and OX 100mg/m2) on Days 2 and 16 of each 28-day treatment cycle during cycles 1 and 2. Thereafter, MT-3724 will be administered weekly on Days 1, 8, 15, and 22 of each cycle with GEMOX on Days 2 and 16 for cycles 3 and 4. The study is currently ongoing. Eligible subjects will be recruited across multiple sites in North America; additional sites in other global regions may be included if necessary. Disclosures Burnett: Molecular Templates, Inc.: Employment. Strack:Molecular Templates, Inc.: Employment. Lehner:Molecular Templates, Inc.: Employment. Higgins:Molecular Templates, Inc.: Employment, Equity Ownership. Katz:Dova: Consultancy; Stemline: Speakers Bureau.