Abstract Background: Acute myeloid leukemia (AML) remains a formidable challenge in hematology, particularly for patients with relapsed or refractory (R/R) disease, where treatment options are limited and outcomes remain poor. Outcomes are dismal in patients with HOXA9/MEIS1 upregulated biology with comutations in FLT3. Combinations of menin- with FLT3 inhibitors are currently being evaluated in the clinic, but concerns remain regarding overlapping toxicities. GB3226 is a first-in-class, orally bioavailable dual inhibitor targeting the ENL-YEATS domain and FLT3, two key drivers of leukemogenesis. ENL (MLLT1), a chromatin reader protein, binds to acetylated histones through the YEATS domain and is crucial for sustaining oncogenic gene expression in leukemia. Genetic or pharmacological disruption of ENL-YEATS reduces leukemia burden. FLT3, a receptor tyrosine kinase overexpressed in most AML blasts. Roughly 30% of newly diagnosed adult AML patients exhibit FLT3 mutations. Dual inhibition of ENL-YEATS and FLT3 may offer superior efficacy. Preclinical studies have demonstrated GB3226's high-affinity binding to ENL-YEATS and FLT3. In relevant AML models and patient-derived in vitro models, GB3226 achieved sustainable tumor regression, and reduced the expression of HOXA9/MEIS1 target gene expression. These compelling preclinical results support the clinical evaluation of GB3226 in R/R AML, addressing a significant unmet medical need. Objectives: Study GB3226-DEV-001 (NCT07084584) is a Phase 1/2, open-label, dose-escalation and expansion study of GB3226 in the treatment of R/R AML. Phase 1 will be an all-comers study, including a broad range of R/R AML patients, whereas Phase 2 inclusion may be restricted to specific genetic subtypes guided by emerging data. The primary objectives of the Phase 1 study are to evaluate the safety, tolerability, and pharmacokinetics (PK)of GB3226 and identify the recommended Phase 2 dose (RP2D). Phase 2 of the study aims at assessing the efficacy of GB3226, measured by the rate of complete remission (CR) and CR with partial hematologic recovery (CRh). Additionally, the study will explore pharmacodynamic (PD) markers in peripheral blood and bone marrow to elucidate GB3226's biological effects and identify potential biomarkers predictive of clinical response. Methods: This open-label, multicenter, seamless Phase 1/2 study will enrol adult patients (aged ≥18 years) with R/R AML, who have failed at least one prior line of therapy (e.g., chemotherapy, venetoclax-based regimens). Phase 1 employs a dose-escalation design across three cohorts to assess the impact of CYP3A4 inhibitors on GB3226 PK and safety and define the maximal tolerated dose (MTD).Cohort A: No CYP3A4 modifiersCohort B: Coadministration with strong CYP3A4 inhibitors (e.g., voriconazole, and posaconazole)Cohort C: coadministration with moderate CYP3A4 inhibitors (e.g., isavuconazole) GB3226 is administered orally once daily in 28-day cycles. Dose escalation follows a rolling-6 design. The RP2D will be selected by a separate data and safety monitoring committee considering the totality of the safety, efficacy, and PK/PD data. Up to 126 patients may be enrolled in Phase 1, depending on dose levels tested and potential backfill cohorts. Phase 2 aims to evaluate efficacy at the RP2D using Simon's two-stage design, starting with 38 efficacy-evaluable patients. If ≥5 patients achieve CR or CRh, an additional 26 patients will be enrolled, totaling 64, with up to 20 more if further data are needed, for a maximum of 84 patients in Phase 2. Extensive PD assessments, including MYC, MEIS1, and HOXA9, pFLT3, pSTAT5, CD11b and CD14 in addition to a wide RNA Seq panel, will be examined. Conclusion: GB3226 is the first clinical-stage agent designed to inhibit ENL-YEATS (MLLT1) and FLT3 simultaneously. This dual-targeting strategy aims to overcome limitations observed with single-pathway agents, including menin- and FLT3 resistance mutations, and incomplete suppression of leukemic stemness. The present clinical trial is designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of GB3226. If successful, GB3226 could offer a novel, differentiated therapeutic modality for the treatment of AML, an orphan disease with high unmet need.
Maiti et al. (Mon,) studied this question.