Trial Investigates a Novel Engineered Toxin Body, Lenalidomide Combo in NHL

A phase 2a study (NCT03645395) is recruiting patients with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL) to receive the combination of MT-3724, a novel CD-20-targeting engineered toxin body (ETB) and lenalidomide (Revlimid), according to a poster presented at the American Association for Cancer Research Advances in Malignant Lymphoma Meeting.

The trial is multicenter, open-label, and multiple-doseinvestigation of the tolerability of MT-3724 and lenalidomide together, including the maximum tolerated dose (MTD), as well as the safety of this combination. The secondary end points are tumor response, pharmacokinetics, pharmacodynamics, and immunogenicity.

The patients entered in this study must have received 1 or more approved therapies for NHL and have measurable disease by Lugano criteria. Patients who have progressed following autologous stem cell transplant, allogeneic stem cell transplant, or chimeric antigen receptor T-cell therapy are eligible to the trial.

“Serum rituximab [Rituxan] level must be negative, that is less than 500 ng/mL at screening because rituximab competes with MT-3724 for binding to CD20,” Thomas Strack, MD, senior vice president of Clinical Development at Molecular Templates, Inc. and an investigator on the study, said in the presentation.

The study is designed as a 2-part analysis; part 1 is the dose-escalation arm, and part 2 is the dose-expansion arm for the maximum tolerated dose. There will be 5 cohorts in the dose-escalation arm after 1 to 35 days of screening prior to C1D1 to define the MTD. Patients in cohort 1 will receive 10 μg/kg per dose of MT-3724 and lenalidomide, cohort 2 will receive 25 μg/kg, cohort 3 will receive 20 μg/kg, cohort 4 will receive 25 μg/kg, and cohort 5 will receive 50 μg/kg. These cohorts will include up to 24 patients with NHL.

Patients in cohorts 1, 2, and 3 will receive the study agent for 1 hour intravenously 3 times weekly for 2 weeks, and lenalidomide will be given orally at 25 mg daily on days 1 through 21 of the 28-day treatment cycle. In subsequent cycles, MT-3724 will be given once weekly with the same lenalidomide dosing.

The protocol was amended for cohort 4 and 5 so that in the first 2 cycles, the anti-CD20 regimen will be given to patients biweekly before switching to weekly dosing schedules for subsequent cycles, according to Strack.

Part 2 will confirm the safety and tolerability of the combination with the MTD from part 1 in up to 40 patients with CD20-positive relapsed or refractory diffuse large b-cell lymphoma.

Patients will be excluded from the trial if they have received anti-CD20 monoclonal antibodies such as rituximab in the 84 days prior, obinutuzumab (Gazyva) in the 184 days prior, or ofatumumab (Kesimpta) in the 88 days prior. They will also not be included if there is current evidence of acute or chronic graft-versus-host disease.

This novel drug is made of anti-CD20 single-chain variable fragment which is genetically fused to Shiga-like toxin A subunit (SLTA). MT-3724 is capable of efficient internalization once it binds to CD20 and can induce potent direct cell-kill through enzymatic ribosome inactivation.

ETBs are made of a proprietarily engineered form of SLTA genetically fused to antibody-like domains, Strack explained. “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 enzymatic and permanent inactivation ribosomes.”

Currently, this agent is being investigated in 3 phase 2 studies for relapsed or refractory diffuse large B-cell lymphoma. One is a monotherapy trial (NCT02361346) and another is MT-3724 in combination with gemcitabine (Gemzar) and oxaliplatin (NCT03488251).

_Reference:

_{Tache J, Katz DA, Mazumder A, et al. A phase 2a open-label study of MT-3724, a novel CD20-targeting engineered toxin body, in combination with lenalidomide (LEN) in subjects with relapsed or refractory B-cell non-Hodgkin lymphoma (NHL). Poster presented at: American Association for Cancer Research Virtual Meeting Advances in Malignant Lymphoma Meeting; August 17-19, 2020. Abstract PO-63. Accessed August 25, 2020.}