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".

This protocol encompasses two phase 3, randomized, double-blind, placebo-controlled clinical studies to assess the efficacy, safety, and tolerability of ziftomenib in combination with: (a) the standard of care (SOC) nonintensive regimen (venetoclax [ven]+azacitidine [aza]) in untreated adults with nucleophosmin 1 mutated (NPM1-m) acute myeloid leukemia (AML); or (b) the SOC intensive regimen (cytarabine+daunorubicin induction, referred to here as 7+3, and cytarabine consolidation) in untreated adults with NPM1-m or lysine[K]-specific methyltransferase 2A rearranged (KMT2A-r) AML, as well as a maintenance phase.

Nonintensive Therapy Study (Ven+Aza)

Eligible NPM1-m patients will be enrolled and randomized to receive:

• Arm A: Ziftomenib in combination with ven+aza or
• Arm B: Placebo in combination with ven+aza.

Patients will be randomized to treatment arms in a double-blind manner.

Intensive Therapy Study (Cytarabine+Daunorubicin)

Eligible NPM1-m or KMT2A-r patients will be enrolled and randomized to 1 of the following treatment arms:

• Arm A: Ziftomenib+7+3 (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance) or
• Arm B: Ziftomenib+7+3 (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance) or
• Arm C: Placebo+7+3 (induction), placebo+cytarabine (consolidation), placebo (maintenance).

Patients will be randomized to treatment arms in a double-blind manner.

Key Inclusion Criteria:

The following criteria apply to both the Nonintensive Therapy Study and the Intensive Therapy Study unless otherwise noted:

• Age ≥18 years at time of signing the informed consent form.

• Diagnosis of AML per the 2022 WHO Classification of Hematolymphoid Tumors (5th Edition).

• Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.

• Adequate liver and kidney function according to protocol requirements.

• A female of childbearing potential must agree to use adequate contraception from the time of screening through 180 days following the last dose of study intervention. A male with a female partner of childbearing potential must agree to use abstinence or adequate contraception from the time of screening through 90 days following the last dose of study intervention.

• NONINTENSIVE THERAPY STUDY ONLY (VEN+AZA):

  1. Documented NPM1-m.

  2. Patients considered ineligible for Intensive Therapy defined by the following:

     • i. Age ≥75, OR
     • ii. Age <75 with an ECOG performance status of 2 or cardiac, renal, or hepatic impairment per protocol criteria.

• INTENSIVE THERAPY STUDY ONLY (7+3):

  1. Documented NPM1-m or KMT2A-r (KMT2A-r patients with a partial tandem duplication are not eligible).
  2. Documented FLT3 wild-type or ITD ratio <0.05 OR ineligible to receive FLT3-targeted therapy (medically ineligible or mutation in which FLT3 inhibition is not SOC). Lack of access to an FLT3 inhibitor is not considered "ineligible" for FLT3-targeted therapy.
  3. Ejection fraction of ≥50%.
  4. Fit for Intensive Therapy per Investigator opinion.

Key Exclusion Criteria:

• Prior therapy for AML (except hydroxyurea or leukapheresis for WBC control).

• Diagnosis of acute promyelocytic leukemia (APL), blast phase chronic myeloid leukemia, or isolated myeloid sarcoma.

• Known history of BCR-ABL mutation.

• History of other active concurrent malignancies prior to study entry except:

  1. Basal cell skin cancer or localized squamous cell cancer of the skin
  2. Previous malignancy confined and locally resected (or treated with other modalities) with curative intent
  3. Prostate or breast cancer receiving adjuvant hormonal therapy.

• Active central nervous system (CNS) involvement by AML.

• Clinical signs/symptoms of leukostasis or white blood cells (WBC) >25×10^9/L prior to start of ziftomenib/placebo. Note: Hydroxyurea and/or leukapheresis are permitted to meet this criterion.

• Known uncontrolled HIV infection or known active hepatitis B virus, hepatitis C virus infection, or other uncontrolled infection.

• Uncontrolled intercurrent illness including but not limited to, cardiac illness as defined in the protocol.

• Women who are pregnant or lactating.