FDA Pauses Trial Evaluating MT-0169 in R/R Multiple Myeloma and Lymphoma

The FDA has placed a partial clinical hold on a phase 1 study (NCT04017130) evaluating MT-0169 as treatment for relapsed or refractory multiple myeloma and non-Hodgkin lymphoma based on previous reports of cardiac adverse effects (AEs) in 2 patients, according to a press release from Molecular Templates, Inc.¹

"We look forward to sharing these data with the FDA and are confident in the benefit-risk profile of MT-0169 at these lower doses," according to the manufacturers of MT-0169.

Investigators will not enroll any new patients until the FDA lifts its partial hold, although those currently enrolled on the trial will continue to receive treatment.

Of the patients who received 50 mcg/kg of MT-0169, 1 had asymptomatic grade 2 myocarditis, and 1 other had asymptomatic grade 3 cardiomyopathy. Both patients had full recoveries within 2 months of these AEs following dose reduction to 5 mcg/kg. Investigators observed no grade 4 or 5 AEs at the 50 mcg/kg dosing level.

Investigators continued to administer MT-0169 at 5 mcg/kg to patients with relapsed multiple myeloma after filing a protocol amendment in January 2022. Four patients who received 5 mcg/kg of MT-0169 had no AEs greater than grade 1, and 1 patient had a very good partial response that progressed to a stringent complete response (CR) while remaining on study treatment for more than 7 months. Additionally, 3 patients receiving 10 mcg/kg of the agent experienced no cardiac AEs, although 1 patient at this dosing level had transient grade 2 diarrhea.

The FDA has requested investigators to provide explanation on the 2 patients who experienced cardiotoxicity, justification for revising the dosing level to 5 mcg/kg, and supply data demonstrating the clinical benefit-to-risk ratio observed with lower doses of MT-0169.

“Patient safety is our highest priority,” Roger Waltzman MD, chief medical officer at Molecular Templates, said in the press release. “The 5 and 10 mcg/kg cohorts have been completed and we have not observed any cardiac [AEs] or other serious [AEs] at these lower doses. One patient dosed at 5 mcg/kg is in a stringent [CR] and is in his seventh month of therapy. We look forward to sharing these data with the FDA and are confident in the benefit-risk profile of MT-0169 at these lower doses.”

MT-0169 is a second generation engineered toxin body.² Moreover, it is a single-chain variable fragment that was designed with a high affinity for CD38, allowing for fusion to the enzymatically deimmunized Shiga-like toxin A subunit. Investigators believe the design of MT-0169 may allow it to overcome the primary mechanisms of tumor resistance to daratumumab (Darzalex).

Investigators of the open-label phase 1 study evaluated the safety, tolerability, efficacy, and pharmacokinetics of MT-0169 in patients with relapsed or refractory multiple myeloma or non-Hodgkin lymphoma.

In the dose escalation portion of the trial, patients received MT-0169 intravenously every 7 days or every 14 days in a 28-day treatment cycle. In the dose expansion portion of the trial, experimental arms included weekly or biweekly dosing for patients with non-Hodgkin lymphoma, weekly or biweekly dosing for those with multiple myeloma that was relapsed or refractory to daratumumab, and weekly dosing for those with multiple myeloma who have not been exposed to anti-CD38 therapy.

The primary end points of part 1 included the maximum tolerated dose or recommended phase 2 dose of MT-0169, dose-limiting toxicities, and treatment-related dose toxicities; overall response rate represented a primary end point in part 2 of the study. Secondary end points included clinical benefit rate, disease control rate, and progression-free survival.

Patients 18 years and older with relapsed or refractory multiple myeloma and measurable disease were eligible for enrollment on part 1 of the trial. Patients also needed to have an ECOG performance status of 0 or 1.

References

1. Molecular Templates announces partial clinical hold for phase 1 study of MT-0169. News release. Molecular Templates, Inc. April 7, 2023. Accessed April 11, 2023. bit.ly/3A8db9P
2. MT-0169. MTem Molecular Templates. Accessed April 11, 2023. bit.ly/3KQCeUL