A Phase 1, Open-Label, Dose Escalation and Dose Expansion, Multicenter Clinical Trial to Evaluate the Safety, Pharmacokinetics, Pharmacodynamics, and Preliminary Efficacy of Lomonitinib (ZE46-0134) in Adults with FLT3-Mutated Relapsed or Refractory Acute Myeloid Leukemia

Background: Lomonitinib is a highly potent and selective pan-FLT3/IRAK4 inhibitor that targets clinically relevant FLT3 mutations (ITD, TKD) including the gatekeeper mutation, as well as IRAK4, a putative escape pathway for FLT3-driven acute myeloid leukemia (AML). In vitro studies with FLT3-mutated cell lines demonstrated potent inhibition and differential decrease of FLT3 protein expression as compared to gilteritinib. Multiple in vivo studies with both xenograft and syngeneic immune-competent murine models show that lomonitinib has superior efficacy to gilteritinib in FLT3-ITD and gatekeeper mutation-dependent disease and has synergistic efficacy in combination with Bcl-2 or menin inhibitors. Unlike gilteritinib, lomonitinib had minimal toxicity in rodent toxicology studies at exposures in excess of the anticipated therapeutic dose. A first-in-human clinical trial of lomonitinib in healthy volunteers was initiated in August 2023 that demonstrated favorable pharmacokinetic (PK) and safety profiles with dose-proportional increases in systemic exposure, FLT3 target engagement, and no treatment-related adverse events. Furthermore, little PK interaction was observed with proton-pump or CYP3A4 inhibitors. The safety profile of lomonitinib enables novel rapid FLT3 engagement by using a loading dose (5-fold higher than the maintenance dose) which is not possible with other long half-life FLT3 inhibitors with less favorable therapeutic indices. A phase 1b study in relapsed/refractory (R/R) AML with mutated FLT3 is currently underway as part of the The Leukemia & Lymphoma Society’s Beat AML Master Trial.

Study Design and Methods: This is a US-based, multicenter, sub-study of the Beat AML Master Trial (NCT03013998) in which R/R AML patients age ≥ 18 years with an identifiable FLT3 mutation are assigned an investigational therapy based on cytogenetic and central genomic analysis. Patients must have received gilteritinib or were eligible to receive gilteritinib. In this phase 1b study, the primary objective is to determine the maximum tolerated dose (MTD) or biologically effective dose (BED) of lomonitinib using a standard 3+3 design based on dose-limiting toxicities with escalation to 6 possible dose levels of lomonitinib. The secondary objectives are to assess safety and tolerability, PK, overall composite response, overall survival, transplant rate and duration of remission. The study will be conducted in two parts, dose escalation (part 1) and expansion (part 2). The study is currently recruiting for part 1.

In part 1, cycle 1 will be initiated at a loading dose of lomonitinib for 1 or 2 days administered at the study site under supervision. Patients will then be administered a maintenance dose of lomonitinib for the remainder of cycle 1 for up to 28 days per cycle. All days of cycles 2 to 24 will be dosed at the assigned maintenance dose of lomonitinib. At the start of each dose cohort, 3 patients will be enrolled sequentially with patients starting at least 24 hours apart. All safety data will be reviewed at the end of the dose limiting toxicity (DLT) period for all 3 patients. Patients who have ≥ 5% blasts in the marrow after cycle 1 can receive up to 2 additional cycles of therapy in the absence of disease progression. Patients may continue study treatment for up to 24 cycles unless lomonitinib is no longer tolerated, patients meet any of the criteria for discontinuation or have disease progression.

In part 2, 30 patients will enroll across 2 dose cohorts (15 patients per cohort) as part of the dose expansion. Lomonitinib will be dosed as described in part 1 of the study. The doses used in part 2 of the study will be determined based on the data from part 1 of the study. A final recommended phase 2 dose (RP2D) will be selected based on overall safety and tolerability, clinical activity and available PK/PD data. The RP2D may or may not be the same as the MTD identified during dose escalation.

Exploratory objectives include assessment of lomonitinib PK and its correlation with response and toxicities. The study will evaluate the impact of minimal residual disease, as measured by central flow cytometry. Pharmacodynamic biomarkers of potential interest that will be assessed include changes in phosphorylation of FLT3/STAT5/MAPK, and cytokine profile. Next-generation sequencing will identify the genomic features of responding, non-responding, and relapse patients.