Azacitidine (AZA)

The purpose of this study is to assess how bleximenib and Venetoclax (VEN)+ Azacitidine (AZA) works as compared to placebo and VEN+AZA alone for the treatment of participants with newly diagnosed Acute Myeloid Leukemia (AML) with a mutation in the NPM1 or KMT2A gene.

This is a phase II, open-label, multi-center study evaluating the efficacy and safety of sonrotoclax (SA) in combination with azacitidine (AZA) plus individualized targeted or chemotherapeutic agents in adult participants with newly diagnosed acute myeloid leukemia (AML). Eligible participants will be stratified into different treatment arms based on genetic background (FLT3/IDH1 mutation status) and fitness for intensive chemotherapy. All participants will receive sonrotoclax with dose escalation from 20 mg/day to 320 mg/day, followed by maintenance dosing, which may be temporarily held by the investigator from Day 14 to Day 28 of each 28-day cycle based on the participant's condition, combined with azacitidine 75 mg/m²/day intravenously on Days 1-7. For participants fit for intensive chemotherapy, additional anthracycline (daunorubicin 60 mg/m²/day or idarubicin 10 mg/m²/day on Days 1-3) will be administered. For participants with FLT3 mutations, gilteritinib 80 mg once daily on Days 1-14 will be added; for those with IDH1 mutations, ivosidenib 500 mg once daily on Days 1-28 will be added.

Ziftomenib is an investigational drug in development for the treatment of patients with acute myeloid leukemia (AML) with eligible genetic alterations. Ziftomenib is a type of therapy known to target the menin pathway in cancer cells. This protocol has 2 separate studies that will investigate the benefits and risks of adding ziftomenib to standard-of-care (SOC) AML treatments in patients with certain genetic mutations who have not received any treatment for their AML. In the first study, the Nonintensive Therapy Study, older patients or those with serious medical problems will receive the SOC therapies venetoclax (ven) and azacitidine (aza), plus either ziftomenib or a placebo. In the second study, the Intensive Therapy Study, medically fit patients will receive (a) the SOC therapies cytarabine and daunorubicin, plus either ziftomenib or a placebo during a first treatment phase called induction, (b) cytarabine plus either ziftomenib or a placebo during a second treatment phase called consolidation, and (c) ziftomenib or a placebo during a third treatment phase called maintenance. The physician will determine which study is the appropriate treatment for the patient, but neither the patient nor their physician will know whether the patient has been assigned to receive ziftomenib or a placebo. This design is called "double-blinded".