Phase 2a/b Dose Escalation and Expansion Study of MT-3724, a Novel CD20-Targeting Engineered Toxin Body, in Subjects with Relapsed or Refractory Follicular Lymphoma

Background: Engineered toxin bodies (ETBs) are a distinct class of targeted immunotoxins in development by Molecular Templates as anti-cancer 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 A subunit (SLT-A). MT-3724 is comprised of an anti-CD20 single-chain variable fragment genetically fused to SLT-A and is capable of both efficient internalization once bound to CD20 and the induction of potent direct cell-kill via enzymatic ribosome inactivation. In a Phase 1/1b dose escalation/expansion study of MT-3724 monotherapy in subjects with heavily pretreated (including CD20 monoclonal antibodies) relapsed or refractory B-cell non-Hodgkin lymphoma (r/rNHL), the most common grade ≥3 treatment-related adverse events were myalgia and neutropenia (n=3, each). Dose-limiting toxicities (DLTs) were indicative of innate immune response. In subjects with r/rNHL who had negative rituximab serum concentrations there was a 38% objective response rate (Hamlin et al. ASH 2019). MT-3724 is currently being studied in five ongoing (three actively recruiting, two in development) Phase 2 studies for r/rNHL including the present study which will evaluate the safety and efficacy of MT-3724 in a population of subjects with r/r follicular lymphoma (r/r FL).

Study Design and Methods: This Phase 2a/b study will evaluate MT-3724 in adults with histologically confirmed, CD20+ r/r FL. Eligible subjects must have previously received ≥2 prior systemic therapies, including an anti-CD20 treatment. Subjects with Grade 3b FL, central nervous system or leptomeningeal involvement, or recent treatment with rituximab (within 84 days of study initiation; if received within 12-37 weeks of start of treatment, serum rituximab level must be confirmed to be negative [<500 ng/mL]), obinutuzumab (within 184 days), or ofatumumab (within 88 days) are not eligible. The washout period for these anti-CD20 antibodies is required due to binding competition with MT-3724 for the CD20 epitope. The primary objective of phase 2a will be to evaluate the safety of MT-3724 and to determine the recommended phase 2 dose (RP2D) based on sequential enrollment of six subjects into up to three cohorts; each cohort will have different step-up MT-3724 dose schedules based on DLTs observed and their timing; the primary objective of phase 2b will be to determine the efficacy (overall response rate) of MT-3724 in subjects with r/r FL. Secondary endpoints will include duration of response, disease control rate, progression-free survival, overall survival, and the percentage of subjects who discontinue MT-3724 treatment to receive stem cell transplant or chimeric antigen receptor T cell therapy for which they were previously ineligible. Safety analysis will include the frequency, severity, and time to onset of adverse events. Phase 2a (Part 1) will comprise safety run-in cohorts consisting of ≥2 cohorts with six subjects each, which will be enrolled sequentially (Figure 1). In Cycle 1/Cohort 1, subjects will receive escalating doses (10, 25, 50, and 75 µg/kg) of MT-3724 thrice-weekly (TIW) over the course of a 32-day cycle. In all cohorts, subsequent cycles will be 28 days long, with once-weekly MT-3724 administration. Step down cohorts will be enrolled in the event of DLTs, with reductions in either the number of weekly administrations or the maximum dose (the latter to be implemented in cohorts that exceed the monotherapy maximum tolerated dose [50 µg/kg]); this will be determined by the timeline of DLT emergence. If Cohort 1 is tolerable, Cohort 2 will be enrolled with dose escalation up to 100 µg/kg. Development of and timing of DLTs will be used to identify the RP2D for Part 2, which will comprise a dose expansion cohort. Enrollment is anticipated to initiate in December 2020 globally.