A First-in-Human Phase 1/2 Study of the Menin-KMT2A(MLL1) Inhibitor BN104 in Adult Patients with Relapsed or Refractory Acute Leukemia

Introduction: BN104 is a novel, highly efficient and non-covalent menin inhibitor. The interaction between Menin and Mixed Lineage Leukemia (MLL) fusion protein can lead to acute leukemia (AL), BN104 has demonstrated in preclinical studies to potently and high selectively target and disrupt the protein-protein interaction between Menin and MLL, thereby inhibiting the growth and proliferation of leukemia cells harboring KMT2A gene rearrangements (KMT2Ar) or NPM1 mutant (NPM1m). BN104 has shown very low risk of QTc prolongation and a wide therapeutic window in preclinical studies, thus may provide advantages over other compounds currently in clinic. We here report initial data from Phase (Ph) 1 dose escalation and dose optimization cohorts in patients (pts) with relapsed/refractory (R/R) AL. Methods: A multicenter, open-label Ph 1/2 study (NCT06052813) is an ongoing to evaluate safety, efficacy, pharmacokinetics, and pharmacodynamics (PD) of BN104 in R/R AL adult pts in China. The Ph1 dose escalation part has completed, while dose optimization portion is ongoing. BN104 is administered orally, once or twice daily, in 28-day cycles. Adverse events (AEs) were graded by CTCAE v5.0. Responses were investigator-assessed per ELN2022. Results: As of data cutoff (30Jun2024), a total of 20 pts with R/R acute myeloid leukemia (AML) have been enrolled. Dose escalation began with a pilot cohort at 200 mg qd and escalated up to 600 mg bid level, including 1 pt in 200 mg qd group, 3 pts in 200 mg bid group, 13 pts in 400 mg bid group, and 3 pts in 600 mg bid group. The median age was 54.5 (range: 19-76) years with 55% female. All pts were R/R AML with a median bone marrow blasts percentage of 38% (range: 9.5%-95%) at screening. The median number of prior lines of treatment was 3 (range: 1-8), including all pts had been treated with Venetoclax, and 4 (20%) pts had allogeneic stem cell transplant. KMT2Ar, NPM1m or NUP98r was present in 12 (60%), 5 (25%) and 2 (10%) pts, respectively, with 1 pt had both KMT2Ar and NPM1m. No pt had dose-limiting toxicity (DLT) event within the 28-day DLT-assessment window. Eighteen (18 [90%]) pts reported at least one treatment-emergent AEs (TEAEs) with Grade ≥3 TEAE being 60%. The most common TEAEs (≥20%) were vomiting (7 [35%]), nausea (6 [30%]), pneumonia, hypokalemia, hypoalbuminemia, blood creatinine increased, alanine aminotransferase increased, blood alkaline phosphatase increased, blood lactate dehydrogenase increased, pyrexia, febrile neutropenia and somnolence (4 [20%] each). Grade≥3 treatment-related AEs (TRAEs) were observed in 7 (35%) pts among whom febrile neutropenia and pneumonia occurring in 3 (15%) and 2 (10%) pts, respectively. Two pts (2 [10%]) reported grade 1 QT prolongation and both events have been resolved. Two pts (2 [10%]) reported grade 2 differentiation syndrome, 1 had recovered and 1 was recovering. Of the 11 pts who completed post-baseline efficacy evaluation, 9 pts presented with target genetic alterations are efficacy evaluable. ORR was 88.9% (8/9) and 3 pts (33.3%) achieved CR/CRh. Time to first response was 0.9months (0.7-3.0; n=8). ≥50% bone marrow blasts reduction was observed in all 9 pts with KMT2Ar or NPM1m. Two pts (2 [22.2%]) went to transplantation. Updated data from dose escalation and dose optimization will be presented. BN104 is absorbed rapidly and peaked at 0.5-1 hour. Drug exposure increased with dose. The PD data have illustrated BN104 on-target biomarker inhibition even at a low dose (200mg bid) which has been translated into clinical benefits. BN104 has shown downregulating the expression of downstream menin-related leukemogenic genes (i.e., HOXA, MEIS1) and upregulating the expression of genes associated with differentiation (i.e., CD11b). Furthermore, BN104 also inhibits FLT3 expression, which supports the theory of combination approach with a FLT3 inhibitor. Conclusions: Based on preliminary results from the dose escalation part, the 400 mg bid and 600 mg bid dose groups were selected for dose optimization. This FIH Phase 1/2 study preliminary data have demonstrated that BN104 monotherapy has a tolerable safety profile and promising antileukemic activity in heavily pretreated R/R AML pts harboring KMT2Ar or NPM1m.