FDA Halts Phase 1 Study MT-0169 Due to Unacceptable Toxicity

The FDA has placed a partial clinical hold on the phase 1 study of MT-0169 (NCT04017130), which is investigating the agent in patients with relapsed or refractory (R/R) multiple myeloma (RRMM) or non-Hodgkin lymphoma (NHL).¹

The partial clinical hold is the result of cardiac adverse events that occurred in 2 patients who received the 50 mcg/kg dose of the drug in 2022 and were then reduced to the 5 mcg/kg dose. According to Molecular Templates, Inc, the sponsor of the clinical trial, 4 patients have since been dosed with MT-0169 at 10 mcg/kg and experienced no cardiac events.

Among patients treated with MT-0169 50 mcg/kg, there has been 1 case of asymptomatic grade 2 myocarditis and 1 case of symptomatic grade 3 cardiomyopathy. However, both patients recovered from the adverse events (AEs) within 2 months. There were no grade 4 or 5 toxicities among patients treated with at the 50 mcg/kg dose level.

The cardiac events in the study prompted a protocol amendment, which was filed in January of 2022. The dose of MT-0169 was reduced by 90% to a 5 mcg/kg dose for all patients. Notably, at the 5 mcg/kg dose level, there were no AEs higher than grade 1, and none were cardiac events, according to data from 4 patients. Moreover, 1 patient treated with MT-0169 5 mcg/kg achieved a very good partial response, which later became a stringent complete response. The patient remains on treatment.

Three patients who received MT-0169 at the 10 mcg/kg dose level experienced no cardiac events, but 1 patient developed transient grade 2 diarrhea.

Approximately 144 patients with RRMM or R/R NHL will be enrolled in the phase 1 study of MT-0169, if it is resumed. The study plans to have a dose-escalation phase in which patients with be administered MT-0169 via intravenous (IV) infusion every 7 days on days 1, 8, 15, and 22, in a 28-day cycle. Treatment in the dose-escalation cohort will continue until progressive disease develops, patients experience unacceptable toxicity, or they withdraw from the study.²

During the dose-expansion phase of the study, patients with RRMM will receive weekly dosing of MT-0169. Treatment will be every 7 days on days, 1, 8, 15, and 22 of a 28-day cycles. The drug will be administered at the recommended phase 2 dose (RP2D). Patients with R/R NHL included in the dose-escalation phase will receive biweekly treatment on days 1 and 15, in a 28-day cycle.

The key primary end points to be explored in part 1 of the study include safety/tolerability, which will be determined based on the maximum-tolerated dose of MT-0169, number of patients with treatment-emergent AEs (TEAEs), dose-limiting toxicities, number of patients with grade 3 or higher TEAEs, the number of patients with serious AEs, number of patients who discontinue treatment, and the number requiring treatment-related dose modifications. The coprimary end points for part 2 of the study include overall response rate, and ORR in the R/R NHL population.

Secondary end points to be investigated during the study include pharmacokinetics, clinical benefit rate, disease control rate, progression-free survival, duration of response, the number of patient with anti-drug antibodies following treatment administration, number of patients with DLTs, number of patients with TEAEs, overall survival, time to response, percentage of patient with a complete or very good partial response to treatment, and measurement of R/R NHL tumor CD38 expression level.

To be eligible for the study, all patients must have a confirmed diagnosis of either RRMM or R/R NHL, measurable disease, and an ECOG performance status of 0 or 1. In addition, patients are required to have a normal QT interval and adequate laboratory values at baseline.

"Patient safety is our highest priority. The 5 and 10 mcg/kg cohorts have been completed and we have not observed any cardiac adverse events or other serious adverse events at these lower doses. One patient dosed at 5 mcg/kg is in a stringent complete response 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," said Roger Waltzman, MD, chief medical officer, Molecular Templates, in a press release.1 "We are excited to see early signs of clinical benefit in this difficult-to-treat patient population."

To resume the phase 1 study of MT-0169 in patients with R/R multiple myeloma and NHL, the sponsor is required by the FDA to provide narratives on the 2 patients who experience cardiac AEs at the 50 mcg/kg dose level. The sponsor must also provide rationale for the amendment to the 5 mcg/kg dose. Lastly, the FDA requires that data assessing the clinical benefit-to-risk ratio of lower-dose MT-0169 be submitted.

_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 12, 2023. https://www.mtem.com/news-media/press-releases/detail/121/molecular-templates-announces-partial-clinical-hold-for}

_{2. A study of MT-0169 in participants with relapsed or refractory multiple myeloma or non-hodgkin lymphoma. ClincalTrials.gov. Updated September 8, 2022. Accessed April 12, 2023. https://clinicaltrials.gov/ct2/show/NCT04017130}