The FDA has removed a partial clinical hold that had been placed on a phase 1 trial investigating the safety and efficacy of MT-0169 as a potential therapeutic option in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma.
The FDA has removed a partial clinical hold that had been placed on a phase 1 trial (NCT04017130) investigating the safety and efficacy of MT-0169 as a potential therapeutic option in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma.1
In April 2023, the regulatory agency made the decision to place the hold after 2 previously disclosed cardiac adverse effects (AEs) were observed in 2 patients who received MT-0169 at 50 μg/kg, which led to a dose reduction to 5 μg/kg.2 These patients had grade 2 myocarditis and asymptomatic grade 3 cardiomyopathy, respectively, and they both recovered within 2 months.
At the time, the FDA requested data on those patients, the reasoning of the revised dose of 5 μg/kg, and information regarding the clinical risk-benefit ratio for the investigative agent at lower doses. With the hold, no new patients were allowed to enroll but those already on the study could still receive treatment. To this end, 4 patients received MT-0169 at 5 μg/kg and 3 patients received the agent at 10 μg/kg. No additional cardiac toxicities were reported.
The decision to lift the hold comes after the regulatory agency reviewed safety data on the program.1
“We are pleased that the FDA has removed the partial clinical hold,” Eric Poma, PhD, chief executive officer and chief scientific officer of Molecular Templates, Inc., stated in a press release. “MT-0169 represents a novel approach to myeloma that is demonstrating good safety with early signs of potential clinical benefit, particularly in the extramedullary setting, where we have seen a stringent complete response in a patient who remains on study for 10 months.”
MT-0169 eliminates CD38-positive tumor cells through by internalizing CD38 and cell destruction through a novel mechanism of action.
A second-generation engineered toxin body, MT-0169, contains a single-chain variable fragment with an affinity for CD38, which is fused to the enzymatically active de-immunized Shiga-like toxin-A subunit.3 The agent is designed to specifically bind to and eliminate CD38-expressing cells, and to overcome the primary mechanisms of tumor resistance to daratumumab (Darzalex). Notably, the agent has been shown to be active in the presence of daratumumab, pointing to its potential to be paired with approved CD38-targeted therapies.
To participate on part 1 of the open-label trial, patients needed to have relapsed or refractory multiple myeloma who progressed on treatment with, are intolerant to, or were not eligible to receive available effective therapies.4 They needed to have received at least 3 previous lines of therapy, or at least 2 prior therapies including a combination of a proteasome inhibitor and an immunomodulatory drug.
For the second part of the trial, MT-0169 was given once weekly on days 1, 8, 15, and 22 of each 28-day treatment cycle. The protocol also features dosing once every 2 weeks on days 1 and 15 of each cycle, with escalating doses beginning at the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) determined by the weekly dose-escalation cohort.
The key objective of the first portion of the trial was to establish the MTD and RP2D, evaluate rates of treatment-emergent AEs, DLTs, rates of grade 3 or higher AEs, serious AEs, discontinuation rates due to toxicities, and instances of treatment-related dose modifications.
The dose-escalation cohorts for 5 μg/kg (n = 4) and 10 μg/kg (n = 3) have been completed, with no cardiac or dose-limiting toxicities observed.1 A patient with extramedullary multiple myeloma that was quad-refractory who received the agent at 5 μg/kg experienced a stringent complete response to treatment; they had a decrease in IgA serum protein, conversion to immunofixation negative status, and resolution of uptake on bone scan of skeletal lesions.
Molecular Templates, Inc., the drug developer, shared that the development of MT-0169 will focus on extramedullary multiple myeloma.