PRIMARY OBJECTIVES:

I. To determine overall survival rate at 1 year of the regimen in patients with newly diagnosed acute myeloid leukemia (AML). (Cohort A) II. To determine the complete remission (CR)/complete remission without recovery of counts (CRi) rate of the regimen in patients with relapsed/refractory AML or high-risk myelodysplastic syndrome (MDS). (Cohort B)

SECONDARY OBJECTIVES:

I. To assess other efficacy endpoints (CR rate, minimal residual disease negativity by flow cytometry, relapse-free survival, event-free survival, and overall survival).

II. To assess proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT).

III. To determine the safety of the combination regimen.

EXPLORATORY OBJECTIVES:

I. To evaluate the impact of baseline genomic alterations on response and survival of the combination regimen.

II. To evaluate clonal evolution from diagnosis to relapse.

INDUCTION (CYCLE 1): Patients receive azacitidine intravenously (IV) over 30-60 minutes or subcutaneously (SC) on days 1-7, venetoclax orally (PO) once daily (QD) on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity.

CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 6 months thereafter.