Studies to Assess Ziftomenib in Combination With Ven+Aza or 7+3 in Patients With Untreated NPM1-m or KMT2A-r AML

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):

• Documented NPM1-m.
• 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):

• Documented NPM1-m or KMT2A-r (KMT2A-r patients with a partial tandem duplication are not eligible).
• 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.
• Ejection fraction of ≥50%.
• 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:

• Basal cell skin cancer or localized squamous cell cancer of the skin
• Previous malignancy confined and locally resected (or treated with other modalities) with curative intent
• 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.