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 Lenalidomide in Subjects with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Introduction:

Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of Non-Hodgkin Lymphoma (NHL) accounting for approximately 30-40% of NHL cases. Approximately 40% of all newly diagnosed DLBCL patients are either refractory or relapsed following initial response to 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 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, and has impeded the development of agents that internalize a cytotoxic payload.

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 <1 nM) and in CB17 SCID and PDX mice (Rajagopalan 2016; Huang 2018).

Given MT-3724's unique ability to kill CD20+ cells by ribosomal inhibition, combining MT-3724 with standard cytotoxic chemotherapy and/or immune modulatory agents may provide enhanced benefit in NHL treatment algorithms. To evaluate this possibility, MT-3724 was tested in combination with Lenalidomide (LEN) to assess additive, synergistic or antagonistic effects in CD20-positive Daudi cell lines. This combination significantly (Ki = 0.40) potentiated cytotoxicity. Based on these results and the known safety profile of MT-3724, LEN was chosen as a combination agent to maximize anti-tumor effects in patients with B-cell NHL while minimizing overlapping toxicity risks.

Study Design and 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 NHL.

The primary objective of this study is to determine the safety and tolerability, including the maximum tolerated dose (MTD), of MT-3724 + LEN. Secondary objectives include pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and tumor response in subjects treated with MT-3724 + LEN.

The study will be conducted in two parts. Part 1 will include MT-3724 dose escalation according to the modified 3+3 design to identify the MTD of MT-3724 in combination with standard doses of LEN and will include up to 24 subjects with histologically confirmed NHL.

Part 2 is designed to confirm 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 would be given in combination with LEN in up to 40 subjects with CD20+ DLBCL. In addition, the PK, PD, immunogenicity and tumor response of MT-3724 + LEN will be evaluated in Part 2.

Eligible subjects will have histologically confirmed, relapsed or refractory CD20+ B-cell NHL that, in the investigator's opinion, could benefit from MT-3724 + LEN therapy. Patients must have received all approved therapies for NHL that are applicable for the patient in the opinion of the treating physician and must have measurable disease by Lugano Classification for NHL. 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. Serum rituximab level must be negative (<500 ng/mL) at screening.

Subjects will receive MT-3724 IV infusions over 1 hour on Days 1, 3, 5, 8, 10 and 12 and will receive LEN on days 1-21 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 continued LEN dosing on Days 1-21 for cycles 3 to 6.

The study is currently ongoing. Eligible subjects will be identified and treated through competitive enrollment at multiple study centers in North America.