First-in-Human Study of Menin Inhibitor SNDX-5613 in MLL-Rearranged and NPM1-Mutant Acute Leukemia

The first-in-human phase 1/2 AUGMENT 101 study evaluated the safety and antileukemic activity of the menin inhibitor SNDX-5613 in patients with relapsed/refractory mixed-lineage leukemia (MLL)-rearranged and nucleophosmin1 (NPM1)-mutated acute leukemias. Communicated results of the completed phase 1 component of the study are summarized here.

The study included 2 parallel dose-escalation cohorts: patients in arm A received strong CYP3A4 inhibitors and those in arm B did not. All patients must have had MLL-rearranged or NPM1-mutated leukemias. Dose escalation was achieved using a “rolling 6” design with expansion at efficacious doses. Eligible patients received SNDX-5613 (orally every 12 hours) in continuous 28-day cycles. Patients in arm A received doses of 113 mg (n = 1), 226 mg (n = 6), 276 mg (n = 10), and 339 mg (n = 8); patients in arm B received 113 mg (n = 16), 163 mg (n = 6), and 226 mg (n = 7) doses. The primary objectives of the phase 1 component of the study were to determine the safety, maximum tolerated dose, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of SNDX-5613; exploratory end points included antileukemic activity and pharmacodynamics (PD). The data cutoff date was June 29, 2021.

A total of 59 patients who had received ≥1 doses of SNDX-5613 were included in the current analysis. The median age was 47 years; 83% (n = 49) of patients had AML, 64% (n = 38) had MLL-rearranged leukemia, and 22% (n = 13) had NPM1-mutated leukemia. Patients had received a median of 4 prior therapies; 59% had received prior venetoclax and 42% had received prior allogeneic stem-cell transplant.

Dose-limiting toxicities of grade 3 QTc prolongation were reported; all these events were clinically asymptomatic. Of the 4 doses that met RP2D criteria, the incidence of grade 3 QTc prolongation was 7% (3/43). Other common treatment-related adverse events (TRAEs) that occurred in >10% of patients were nausea (27%), vomiting (17%), differentiation syndrome (14%), and diarrhea (12%). Overall, grade ≥3 TRAEs occurred in 19% of patients; QTc prolongation (12%) was the most common grade ≥3 TRAE that occurred in >10% of patients, the remainder (anemia, asthenia, diarrhea, fatigue, hypokalemia, neutropenia, thrombocytopenia, tumor lysis syndrome) occurred in only 2% of patients.

In the MLL-rearranged and NPM1-mutated leukemia cohort (n = 51), the overall response rate (ORR) was 55% (n = 28), including a complete response (CR) rate of 16% (n = 8), a CR with partial hematologic recovery rate of 8% (n = 4), a CR with incomplete platelet recovery rate of 14% (n = 7), and a morphologic leukemia-free state rate of 18% (n = 9). Of the 51 patients who achieved composite CR (n = 20), 16 (31%) patients achieved negative minimal residual disease status, assessed locally by flow cytometry or polymerase chain reaction. The ORR rate was 61% (23/38) in the MLL-rearranged leukemia cohort and 38% (3/13) in the NPM1-mutated leukemia cohort. A total of 9 patients received stem-cell transplantation.

PK analysis found that SNDX-5613 showed dose-proportional PK, with increased exposure when the drug was co-administered with a strong CYP3A4 inhibitor. PD assessments showed that SNDX-5613 disrupted menin binding to chromatin, which aligned with its mechanism of action; conversely, and expectedly, patients who had wild-type MLL and NMP1 did not respond to SNDX-5613.

Based on these results, it was concluded that SNDX-5613 demonstrated an acceptable safety profile and promising antileukemic activity in patients with heavily pretreated relapsed/refractory MLL-rearranged and NPM1-mutated acute leukemias.

Source: Stein EM, et al. ASH 2021; abstr 699.

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