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

Phase 3 Randomized, Double-blind, Placebo-controlled Studies Assessing Ziftomenib in Combination With Either Standard of Care Nonintensive (Venetoclax+Azacitidine) or Intensive (7+3) Therapy in Patients With Untreated NPM1 Mutated or KMT2A Rearranged Acute Myeloid Leukemia

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".

Study Overview

• Status: Recruiting
• Conditions: Acute Myeloid Leukemia (AML)
• Intervention / Treatment: Drug: Placebo; Drug: Ziftomenib; Drug: Venetoclax; Drug: Azacitidine (AZA); Drug: Daunorubicin; Drug: Cytarabine (Ara-C)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 1300
• Phase: Phase 3

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Kura Medical Information; Phone Number: 844-KURAONC (844-587-2662); Email: medinfo@kuraoncology.com

Study Locations

• France
  • Béziers, France, 35400
    • Recruiting
    • Centre Hospitalier de Beziers
  • Mulhouse, France, 68100
    • Recruiting
    • Groupe Hospitalier de la Region de Mulhouse et Sud Alsace Hôpital Emile Muller
  • Nantes, France, 44000
    • Recruiting
    • Centre Hospitalier Universitaire de Nantes
  • Saint-Priest-en-Jarez, France, 42270
    • Recruiting
    • Centre Hospitalier Universitaire de Saint Etienne
  • Vandœuvre-lès-Nancy, France, 54510
    • Recruiting
    • Centre Hospitalier Régional et Universitaire de Nancy Hôpitaux de Brabois
• Germany
  • Bad Saarow, Germany, 15526
    • Recruiting
    • HELIOS Klinikum Bad Saarow
• Italy
  • Bologna, Italy, 40138
    • Recruiting
    • L'IRCCS Azienda Ospedaliero - Universitaria di Bologna
• Portugal
  • Braga, Portugal, 1099-023
    • Recruiting
    • Hospital de Braga, Centro Clínico Académico de Braga
• South Korea
  • Busan, South Korea, 49201
    • Recruiting
    • Dong-A University Hospital
  • Daejeon, South Korea, 35015
    • Recruiting
    • Chungnam National University Daejeon Hospital
  • Hwasun, South Korea, 58128
    • Recruiting
    • Chonnam National University Hwasun Hospital
  • Ulsan, South Korea, 44033
    • Recruiting
    • Ulsan University Hospital
• Spain
  • Madrid, Spain, 28041
    • Recruiting
    • Hospital Universitario 12 de Octubre
  • Seville, Spain, 41013
    • Recruiting
    • University Hospital Virgen Del Rocio S.L.
  • Valencia, Spain, 46026
    • Recruiting
    • Hospital Universitario y Politécnico La FE
• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Recruiting
      • Banner MD Anderson Cancer Center
  • California
    • Clovis, California, United States, 93611
      • Recruiting
      • University of California, Fresno
    • La Jolla, California, United States, 92093
      • Recruiting
      • University of California, San Diego
    • Los Angeles, California, United States, 90095
      • Recruiting
      • University of California, Los Angeles
    • Los Angeles, California, United States, 90048
      • Recruiting
      • Cedars-Sinai Medical Center
    • Orange, California, United States, 92868
      • Recruiting
      • University of California, Irvine
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Colorado Blood Cancer Institute
  • Connecticut
    • Hartford, Connecticut, United States, 06106
      • Recruiting
      • Hartford HealthCare Cancer Institute
    • New Haven, Connecticut, United States, 06510
      • Recruiting
      • Yale University School of Medicine
  • Florida
    • Miami, Florida, United States, 33136
      • Recruiting
      • University of Miami
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Moffitt Cancer Center & Research Institute
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • Recruiting
      • University of Kentucky
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Wayne State University School of Medicine
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • Recruiting
      • University of Minnesota
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Recruiting
      • Rutgers Biomedical and Health Sciences
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • Recruiting
      • University of New Mexico
  • New York
    • Buffalo, New York, United States, 14263
      • Recruiting
      • State University of New York at Buffalo
    • New York, New York, United States, 10032
      • Recruiting
      • Columbia University
    • New York, New York, United States, 10065
      • Recruiting
      • Weill Cornell Medical Center
    • New York, New York, United States, 10003
      • Recruiting
      • Icahn School of Medicine at Mount Sinai
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • Recruiting
      • University of North Carolina, Chapel Hill
    • Durham, North Carolina, United States, 27710
      • Recruiting
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Recruiting
      • Ohio State University
  • Oregon
    • Eugene, Oregon, United States, 97401
      • Recruiting
      • Willamette Valley Cancer Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Recruiting
      • University of Pennsylvania
  • Tennessee
    • Memphis, Tennessee, United States, 38120
      • Recruiting
      • Baptist Clinical Research Institute
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Tennessee Oncology
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • TriStar Centennial Medical Center
  • Texas
    • Austin, Texas, United States, 78705
      • Recruiting
      • Texas Oncology-Austin Midtown
    • Dallas, Texas, United States, 75231
      • Recruiting
      • Texas Oncology-Presbyterian Cancer Center
    • Houston, Texas, United States, 77030
      • Recruiting
      • University of Texas
    • San Antonio, Texas, United States, 78240
      • Recruiting
      • Texas Oncology - San Antonio Medical Center
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • University of Virginia School Of Medicine
    • Manassas, Virginia, United States, 20110
      • Recruiting
      • Virginia Cancer Specialists
  • West Virginia
    • Wheeling, West Virginia, United States, 26003
      • Recruiting
      • WVU Medicine Wheeling Hospital
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • Recruiting
      • University of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Recruiting
      • Froedtert & Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nonintensive Therapy Study, Arm A; Ziftomenib in combination with venetoclax+azacitidine	Drug: Ziftomenib; Oral administration; Other Names: KO-539; Drug: Venetoclax; Oral administration; Other Names: Venclexta; Venclyxto; Drug: Azacitidine (AZA); Intravenous or subcutaneous administration; Other Names: Vidaza; Azadine
Placebo Comparator: Nonintensive Therapy Study, Arm B; Placebo in combination with venetoclax+azacitidine	Drug: Placebo; Oral administration; Drug: Venetoclax; Oral administration; Other Names: Venclexta; Venclyxto; Drug: Azacitidine (AZA); Intravenous or subcutaneous administration; Other Names: Vidaza; Azadine
Experimental: Intensive Therapy Study, Arm A; Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), ziftomenib (maintenance)	Drug: Ziftomenib; Oral administration; Other Names: KO-539; Drug: Daunorubicin; Intravenous administration; Other Names: Cerubidine; daunomycin; Drug: Cytarabine (Ara-C); Intravenous administration; Other Names: Cytosar-U; Tarabine PFS; cytosine arabinoside (ara-C)
Experimental: Intensive Therapy Study, Arm B; Ziftomenib+cytarabine+daunorubicin (induction), ziftomenib+cytarabine (consolidation), placebo (maintenance)	Drug: Placebo; Oral administration; Drug: Ziftomenib; Oral administration; Other Names: KO-539; Drug: Daunorubicin; Intravenous administration; Other Names: Cerubidine; daunomycin; Drug: Cytarabine (Ara-C); Intravenous administration; Other Names: Cytosar-U; Tarabine PFS; cytosine arabinoside (ara-C)
Placebo Comparator: Intensive Therapy Study, Arm C; Placebo+cytarabine+daunorubicin (induction), placebo+cytarabine (consolidation), placebo (maintenance)	Drug: Placebo; Oral administration; Drug: Daunorubicin; Intravenous administration; Other Names: Cerubidine; daunomycin; Drug: Cytarabine (Ara-C); Intravenous administration; Other Names: Cytosar-U; Tarabine PFS; cytosine arabinoside (ara-C)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nonintensive Therapy Study: (Primary Endpoint for all countries): Overall survival (OS)	OS	Defined as the time from randomization to date of death from any cause, assessed up to 36 months after last patient inclusion
Nonintensive Therapy Study: (Dual Primary Endpoint for US & US reference countries only): Complete remission (CR)	CR rate per European Leukemia Network (ELN) 2022 criteria per Investigator assessment	Assessed up to 36 months after last patient inclusion
Intensive Therapy Study: (Primary Endpoint for all countries): Event-free survival (EFS)	EFS	Defined as the time from randomization to treatment failure, hematologic relapse following CR, or death from any cause, whichever comes first, assessed up to 36 months after last patient inclusion
Intensive Therapy Study: (Dual Primary Endpoint for US & US reference countries only): Complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) negativity in NPM1-m patients	CR rate per ELN 2022 criteria per Investigator assessment with central BM MRD negativity	Assessed up to 36 months after last patient inclusion

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nonintensive Therapy Study: (EU & EU reference countries only): Complete remission (CR)	CR rate per ELN 2022 criteria per Investigator assessment	Up to 36 months after last patient inclusion
Nonintensive Therapy Study: Bone marrow (BM) measurable residual disease (MRD) negativity	Central BM MRD negativity rate	Up to 36 months after last patient inclusion
Nonintensive Therapy Study: Complete remission (CR) + complete remission with partial hematologic recovery (CRh)	CR + CRh rate per ELN 2022 criteria per Investigator assessment	Up to 36 months after last patient inclusion
Nonintensive Therapy Study: Descriptive statistics of Adverse Events (AEs)	Assessed by NCI-CTCAE v5.0	From start of treatment to 28 days from last dose of ziftomenib or placebo
Nonintensive Therapy Study: Area under the concentration-time curve (AUC) of ziftomenib and venetoclax	To characterize the AUC of ziftomenib and venetoclax	During treatment for up to 36 months after last patient inclusion
Nonintensive Therapy Study: Trough concentration (Ctrough) of ziftomenib and venetoclax	To characterize the Ctrough of ziftomenib and venetoclax	During treatment for up to 36 months after last patient inclusion
Intensive Therapy Study: (EU & EU reference countries only): Complete remission (CR) with bone marrow (BM) measurable residual disease (MRD) negativity in NPM1-m patients	CR rate per ELN 2022 criteria per Investigator assessment with central BM MRD negativity	Up to 36 months after last patient inclusion
Intensive Therapy Study: Overall survival (OS)	OS	Defined as the time from randomization to date of death from any cause, up to 36 months after last patient inclusion
Intensive Therapy Study: Descriptive statistics of Adverse Events (AEs)	Assessed by NCI-CTCAE v5.0	From start of treatment to 28 days from last dose of ziftomenib or placebo
Intensive Therapy Study: Area under the concentration-time curve (AUC) of ziftomenib	To characterize the AUC of ziftomenib	During treatment for up to 36 months after last patient inclusion
Intensive Therapy Study: Trough concentration (Ctrough) of ziftomenib	To characterize the Ctrough of ziftomenib	During treatment for up to 36 months after last patient inclusion
Nonintensive Therapy Study: Health-related patient-reported outcomes (PRO) assessments	Health-related quality of life (HRQoL) was evaluated by EORTC QLQ-C30 global health status/quality of life composite scale in all randomized participants. The QLQ-C30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicated better quality of life (QoL), while higher scores on the symptom scales indicated declining QoL.	Up to 36 months after last patient inclusion
Intensive Therapy Study: Health-related patient-reported outcomes (PRO) assessments	Health-related quality of life (HRQoL) was evaluated by EORTC QLQ-C30 global health status/quality of life composite scale in all randomized participants. The QLQ-C30 is a cancer-specific, self-administered questionnaire that contains 30 questions, covering global, functional, and symptom scales. Scores range from 0 to 100. Higher scores on global and functional scales indicated better quality of life (QoL), while higher scores on the symptom scales indicated declining QoL.	Up to 36 months after last patient inclusion

Collaborators and Investigators

• Sponsor: Kura Oncology, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2025
• Primary Completion (Estimated): November 1, 2031
• Study Completion (Estimated): November 1, 2031

Study Registration Dates

• First Submitted: May 16, 2025
• First Submitted That Met QC Criteria: May 28, 2025
• First Posted (Actual): June 5, 2025

Study Record Updates

• Last Update Posted (Actual): May 12, 2026
• Last Update Submitted That Met QC Criteria: May 8, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Acute Myeloid Leukemia; AML; Leukemia; Untreated AML; Acute Leukemia; Newly diagnosed AML; Hematological malignancy; KMT2A; NPM1; Menin; MLL; Newly diagnosed KMT2A-r AML; Newly diagnosed NPM1m AML; Untreated NPM1m AML; Untreated KMT2A-r AML
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Hemic and Lymphatic Diseases; Leukemia; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Arabinonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Cytarabine; Azacitidine; Daunorubicin; venetoclax
• Other Study ID Numbers: KO-MEN-017; 2025-521314-25-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No