A Phase 2 Study of MT-3724 to Evaluate Safety, Pharmacodynamics and Efficacy of MT-3724 for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-Cell 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). As a direct-kill immunotoxin against CD20, MT-3724 has achieved clinical response in subjects with relapsed NHL regardless of acquired resistance to other treatments. Thus, MT-3724 could be a valuable addition to the armamentarium of treating DLBCL. Study Design and Methods: MT-3724 is being evaluated in this Phase 2 study as monotherapy (NCT02361346) in adult subjects with histologically confirmed, relapsed or refractory DLBCL. The primary objective is to determine the efficacy of MT-3724 as monotherapy based on the overall response rate (ORR) by the revised Lugano Classification for Lymphoma adjusted according to immunomodulatory therapy criteria (LYRIC), hereinafter referred to as "revised Lugano Criteria" (Cheson 2014, 2016). Overall response rate is defined as the proportion of subjects with either a complete response or a partial response as determined by independent, blinded central review. Secondary objectives include safety, progression‐free survival, investigator‐assessed ORR, duration of response, and overall survival as well as pharmacokinetics and pharmacodynamics, immunogenicity, and quality of life. To be eligible, patients must have histologically confirmed, relapsed or refractory DLBCL, have received at least 2 standard of care systemic NHL treatment regimens, and have measurable disease according to the revised Lugano criteria. Since rituximab and MT-3724 compete for the same CD20 domain, subjects must have serum rituximab levels < 500 ng/mL before the start of treatment to allow adequate binding of MT-3724. This single arm phase 2 study is being conducted in three stages, where the first two stages will follow the Simon two-stage optimal design [Simon 1989]. Subjects will be enrolled in successive cohorts with each cohort evaluated for efficacy before opening the subsequent cohort, toward a total sample size of 100 subjects. Subjects will receive MT-3724 as an IV infusion over 1 hour on Days 1, 3, 5, 8, 10 and 12 of a 21-day treatment cycle. All subjects will be treated with a 50 µg/kg/dose of MT-3724, which was the recommended Phase 2 dose, as determined in the Phase 1/1b portion of the trial. Sites are open and recruiting in the US, Canada, and Europe. Disclosures Persky: Sandoz: Consultancy; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee. Musteata:Arensia EM: Other: Principal Investigator; Institute of Oncology: Employment. Strack:Molecular Templates, Inc.: Employment. Burnett:Molecular Templates, Inc.: Employment. Wilson:Molecular Templates, Inc.: Employment. Baetz:Bristol Meyers Squibb: Other: Advisory board; Merck: Other: Advisory board; Gilead: Other: Advisory board; Roche: Other: Advisory board.

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